Shifting Paradigms in the Treatment of Systemic Lupus Erythematosus

Authors

  • Ann E. Clarke, MD, MSc, FRCPC Division of Rheumatology, Cumming School of Medicine, University of Calgary
  • Megan R.W. Barber, MD, PhD, FRCPC Division of Rheumatology, Cumming School of Medicine, University of Calgary
  • Bryce Barr, MD, FRCPC Section of Nephrology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba
  • Kim Cheema, MD, FRCPC Division of Nephrology, Cumming School of Medicine, University of Calgary
  • Nicholas L. Li, MD, PhD, FRCPC Division of Nephrology, Cumming School of Medicine, University of Calgary

DOI:

https://doi.org/10.58931/crt.2024.1248

Abstract

For many years, therapeutic options for patients with systemic lupus erythematosus (SLE) have been extremely limited. However, over the past decade, with the approval of new drugs and several promising phase II trials, treatment paradigms are gradually shifting toward multi‑targeted therapies for lupus nephritis (LN) and earlier usage of biologics in extra-renal lupus. Below, we will present three patient cases that illustrate how, through a multidisciplinary clinic environment, we have incorporated these shifting treatment paradigms into our delivery of care. Finally, we will conclude with a discussion of emerging therapies, which have the potential to further shift, and ultimately transform, treatment paradigms.

Author Biographies

Ann E. Clarke, MD, MSc, FRCPC, Division of Rheumatology, Cumming School of Medicine, University of Calgary

Dr. Ann Clarke is a Professor in the Division of Rheumatology at the University of Calgary and holds The Arthritis Society Chair in Rheumatic Diseases. She is the Founder and Director of the University of Calgary Lupus/Antiphospholipid Syndrome (APS) Centre of Excellence. Her research focuses on the risk and determinants of malignancy in SLE, the economic burden of SLE, and clinical trials of novel therapeutics. Dr. Clarke has published over 450 manuscripts and is very engaged in the training of the next generation of lupus clinicians and investigators. 

Megan R.W. Barber, MD, PhD, FRCPC, Division of Rheumatology, Cumming School of Medicine, University of Calgary

Dr. Megan Barber is a rheumatologist and clinician investigator and the Associate Director of Clinical Trials and Clinical Research for the University of Calgary Lupus Centre of Excellence. Particular research interests include antiphospholipid syndrome and novel lupus therapeutics.

Bryce Barr, MD, FRCPC, Section of Nephrology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba

Dr. Bryce Barr is a nephrologist and Assistant Professor in the Department of Medicine at the University of Manitoba. He specializes in glomerulonephritis, with specific interest in lupus nephritis and ANCA-associated vasculitis and is the principal investigator of the Manitoba Glomerular Diseases Registry.

Kim Cheema, MD, FRCPC, Division of Nephrology, Cumming School of Medicine, University of Calgary

Dr. Kim Cheema is a nephrologist in Calgary, Alberta with clinical expertise in glomerular conditions. She completed her internal medicine and nephrology training in Calgary, which was followed by advanced subspecialty training in Lupus and Vasculitis with Professor David Jayne. 

Nicholas L. Li, MD, PhD, FRCPC, Division of Nephrology, Cumming School of Medicine, University of Calgary

Dr. Nicholas Li is a Nephrologist and Clinical Assistant Professor in the Department of Medicine at the University of Calgary. He received his PhD in human immunology from the University of Alberta and his MD from the University of Calgary, where he also completed Internal Medicine and Nephrology. Dr. Li also pursued advanced fellowship training in Lupus, Vasculitis, and Glomerulonephritis at The Ohio State University under the mentorship of Dr. Brad Rovin.

References

Fanouriakis A, Kostopoulou M, Andersen J, Aringer M, Arnaud L, Bae SC, et al. EULAR recommendations for the management of systemic lupus erythematosus: 2023 update. Ann Rheum Dis. 2024;83(1):15-29. doi: 10.1136/ard-2023-224762. DOI: https://doi.org/10.1136/ard-2024-225617

Kidney Disease: Improving Global Outcomes (KDIGO) Lupus Nephritis Work Group. KDIGO 2024 Clinical Practice Guideline for the Management of Lupus Nephritis. Kidney Int. 2024;105(1S):S1-S69. doi: 10.1016/j.kint.2023.09.002 DOI: https://doi.org/10.1016/j.kint.2023.09.002

Fanouriakis A, Kostopoulou M, Cheema K, Anders HJ, Aringer M, Bajema I, et al. 2019 Update of the Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of lupus nephritis. Ann Rheum Dis. 2020;79(6):713-723. doi: 10.1136/annrheumdis-2020-216924 DOI: https://doi.org/10.1136/annrheumdis-2020-eular.3936

Malvar A, Alberton V, Lococo B, Lourenco M, Martinez J, Burna L, et al. Remission of lupus nephritis: the trajectory of histological response in successfully treated patients. Lupus Sci Med. 2023;10(1):e000932. doi: 10.1136/lupus-2023-000932 DOI: https://doi.org/10.1136/lupus-2023-000932

Furie R, Rovin BH, Houssiau F, Malvar A, Teng YKO, Contreras G, et al. Two-year, randomized, controlled trial of belimumab in lupus nephritis. N Engl J Med. 2020;383(12):1117-1128. doi: 10.1056/NEJMoa2001180 DOI: https://doi.org/10.1056/NEJMoa2001180

Rovin BH, Furie R, Teng YKO, Contreras G, Malvar A, Yu X, et al. A secondary analysis of the Belimumab International Study in Lupus Nephritis trial examined effects of belimumab on kidney outcomes and preservation of kidney function in patients with lupus nephritis. Kidney Int. 2022;101(2):403-413. doi: 10.1016/j.kint.2021.08.027 DOI: https://doi.org/10.1016/j.kint.2021.08.027

Rovin BH, Teng YKO, Ginzler EM, Arriens C, Caster DJ, Romero-Diaz J, et al. Efficacy and safety of voclosporin versus placebo for lupus nephritis (AURORA 1): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2021;397(10289):2070-2080. doi: 10.1016/S0140-6736(21)00578-X DOI: https://doi.org/10.1016/S0140-6736(21)00578-X

Saxena A, Ginzler EM, Gibson K, Satirapoj B, Santillan AEZ, Levchenko O, et al. Safety and efficacy of long-term voclosporin treatment for lupus nephritis in the phase 3 AURORA 2 clinical trial. Arthritis Rheumatol. 2024;76(1):59-67. doi: 10.1002/art.42657 DOI: https://doi.org/10.1002/art.42657

Navarra SV, Guzman RM, Gallacher AE, Hall S, Levy RA, Jimenez RE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377(9767):721-731. doi: 10.1016/S0140-6736(10)61354-2 DOI: https://doi.org/10.1016/S0140-6736(10)61354-2

Furie R, Petri M, Zamani O, Cervera R, Wallace DJ, Tegzova D, et al. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum. 2011;63(12):3918-3930. doi: 10.1002/art.30613 DOI: https://doi.org/10.1002/art.30613

Liu Z, Zhang H, Liu Z, Xing C, Fu P, Ni Z, et al. Multitarget therapy for induction treatment of lupus nephritis: a randomized trial. Ann Intern Med. 2015;162(1):18-26. DOI: https://doi.org/10.7326/M14-1030

Zhou T, Zhang X, Lin W, Lin S. Multitarget Therapy: An Effective and Safe Therapeutic Regimen for Lupus Nephritis. J Pharm Pharm Sci. 2019;22(1):365-375. doi: 10.7326/M14-1030 DOI: https://doi.org/10.18433/jpps30526

Moroni G, Gatto M, Tamborini F, Quaglini S, Radice F, Saccon F, et al. Lack of EULAR/ERA-EDTA response at 1 year predicts poor long-term renal outcome in patients with lupus nephritis. Ann Rheum Dis. 2020;79(8):1077-1083. doi: 10.1136/annrheumdis-2020-216965 DOI: https://doi.org/10.1136/annrheumdis-2020-216965

Tamirou F, Lauwerys BR, Dall’Era M, Mackay M, Rovin B, Cervera R, et al. A proteinuria cut-off level of 0.7 g/day after 12 months of treatment best predicts long-term renal outcome in lupus nephritis: data from the MAINTAIN Nephritis Trial. Lupus Sci Med. 2015;2(1):e000123. doi: 10.1136/lupus-2015-000123 DOI: https://doi.org/10.1136/lupus-2015-000123

Dall’Era M, Cisternas MG, Smilek DE, Straub L, Houssiau FA, Cervera R, et al. Predictors of long-term renal outcome in lupus nephritis trials: lessons learned from the Euro-Lupus Nephritis cohort. Arthritis Rheumatol. 2015;67(5):1305-1313. doi: 10.1002/art.39026 DOI: https://doi.org/10.1002/art.39026

Rovin BH, Furie R, Latinis K, Looney RJ, Fervenza FC, Sanchez-Guerrero J, et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum. 2012;64(4):1215-1226. doi: 10.1002/art.34359 DOI: https://doi.org/10.1002/art.34359

Gomez Mendez LM, Cascino MD, Garg J, Katsumoto TR, Brakeman P, Dall’Era M, et al. Peripheral blood B cell depletion after rituximab and complete response in lupus nephritis. Clin J Am Soc Nephrol. 2018;13(10):1502-9. doi: 10.2215/CJN.01070118. DOI: https://doi.org/10.2215/CJN.01070118

Alshaiki F, Obaid E, Almuallim A, Taha R, El-Haddad H, Almoallim H. Outcomes of rituximab therapy in refractory lupus: a meta-analysis. Eur J Rheumatol. 2018;5(2):118-126. doi: 10.5152/eurjrheum.2018.17096 DOI: https://doi.org/10.5152/eurjrheum.2018.17096

Arora S, Rovin BH. Expert Perspective: An Approach to Refractory Lupus Nephritis. Arthritis Rheumatol. 2022;74(6):915-926. doi: 10.1002/art.42092 DOI: https://doi.org/10.1002/art.42092

Furie RA, Aroca G, Cascino MD, Garg JP, Rovin BH, Alvarez A, et al. B-cell depletion with obinutuzumab for the treatment of proliferative lupus nephritis: a randomised, double-blind, placebo-controlled trial. Ann Rheum Dis. 2022;81(1):100-107. doi: 10.1136/annrheumdis-2021-220920 DOI: https://doi.org/10.1136/annrheumdis-2021-220920

Rovin BH, Furie RA, Ross Terres JA, Giang S, Schindler T, Turchetta A, et al. Kidney Outcomes and preservation of kidney function with obinutuzumab in patients with lupus nephritis: a post hoc analysis of the NOBILITY trial. Arthritis Rheumatol. 2024;76(2):247-254. doi: 10.1002/art.42734 DOI: https://doi.org/10.1002/art.42734

Jayne D, Rovin B, Mysler EF, Furie RA, Houssiau FA, Trasieva T, et al. Phase II randomised trial of type I interferon inhibitor anifrolumab in patients with active lupus nephritis. Ann Rheum Dis. 2022;81(4):496-506. doi: 10.1136/annrheumdis-2021-221478 DOI: https://doi.org/10.1136/annrheumdis-2021-221478

Jayne D, Rovin B, Mysler E, Furie R, Houssiau F, Trasieva T, et al. Anifrolumab in lupus nephritis: results from second-year extension of a randomised phase II trial. Lupus Sci Med. 2023;10(2) :e000910. doi: 10.1136/lupus-2023-000910 DOI: https://doi.org/10.1136/lupus-2023-000910

Wang H, Li T, Sun F, Liu Z, Zhang D, Teng X, et al. Safety and efficacy of the SGLT2 inhibitor dapagliflozin in patients with systemic lupus erythematosus: a phase I/II trial. RMD Open. 2022;8(2):e002686. doi: 10.1136/rmdopen-2022-002686 DOI: https://doi.org/10.1136/rmdopen-2022-002686

Furie RA, Morand EF, Bruce IN, Manzi S, Kalunian KC, Vital EM, et al. Type I interferon inhibitor anifrolumab in active systemic lupus erythematosus (TULIP-1): a randomised, controlled, phase 3 trial. Lancet Rheumatol. 2019;1(4):e208-e219. doi: 10.1016/S2665-9913(19)30076-1 DOI: https://doi.org/10.1016/S2665-9913(19)30076-1

Morand EF, Furie R, Tanaka Y, Bruce IN, Askanase AD, Richez C, et al. Trial of anifrolumab in active systemic lupus erythematosus. N Engl J Med. 2020;382(3):211-221. doi: 10.1056/NEJMoa1912196 DOI: https://doi.org/10.1056/NEJMoa1912196

Kalunian KC, Furie R, Morand EF, Bruce IN, Manzi S, Tanaka Y, et al. A randomized, placebo-controlled phase iii extension trial of the long-term safety and tolerability of anifrolumab in active systemic lupus erythematosus. Arthritis Rheumatol. 2023;75(2):253-265. doi: 10.1002/art.42392 DOI: https://doi.org/10.1002/art.42392

Papachristodoulou E, Kyttaris VC. New and emerging therapies for systemic lupus erythematosus. Clin Immunol. 2024;263:110200. doi: 10.1016/j.clim.2024.110200 DOI: https://doi.org/10.1016/j.clim.2024.110200

Wu D, Li J, Xu D, Merrill JT, van Vollenhoven RF, Liu Y, et al. Telitacicept in patients with active systemic lupus erythematosus: results of a phase 2b, randomised, double-blind, placebo-controlled trial. Ann Rheum Dis. 2024;83(4):475-487. doi: 10.1136/ard-2023-224854 DOI: https://doi.org/10.1136/ard-2023-224854

Wu D, Li J, Xu D, Wang L, Fang J, Ross D, et al. Telitacicept, a human recombinant fusion protein targeting b lymphocyte stimulator (BlyS) and a proliferation-inducing ligand (APRIL), in systemic lupus erythematosus (SLE): results of a phase 3 study. ACR Convergence 2022; 2022 Nov 14; Philadelphia, USA. Available from: https://acrabstracts.org/abstract/telitacicept-a-human-recombinant-fusion-protein-targeting-b-lymphocyte-stimulator-blys-and-a-proliferation-inducing-ligand-april-in-systemic-lupus-erythematosus-sle-results-of-a-phase-3-study/

Shen N, Ignatenko S, Gordienko A, Hernández JC, Agmon-Levin N, Narongroenknawin P, et al. Phase 2 safety and efficacy of subcutaneous (s.c.) dose ianalumab (VAY736; Anti-BAFFR mAb) administered monthly over 28 weeks in patients with systemic lupus erythematosus (SLE) of moderate-to-severe activity. ACR Convergence 2023; 2023 Nov 14; San Diego, USA. Available from: https://acrabstracts.org/abstract/phase-2-safety-and-efficacy-of-subcutaneous-s-c-dose-ianalumab-vay736-anti-baffr-mab-administered-monthly-over-28-weeks-in-patients-with-systemic-lupus-erythematosus-sle-of-moderate-to-severe/

Morand E, Pike M, Merrill JT, van Vollenhoven R, Werth VP, Hobar C, et al. Deucravacitinib, a tyrosine kinase 2 inhibitor, in systemic lupus erythematosus: a Phase II, randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol. 2023;75(2):242-252. doi: 10.1002/art.42391 DOI: https://doi.org/10.1002/art.42391

Merrill J, Tanaka Y, D’Cruz D, Vila-Rivera K, Siri D, Zeng X, et al. Efficacy and safety of upadacitinib or elsubrutinib alone or in combination for patients with systemic lupus erythematosus: a phase 2 randomized controlled trial. Arthritis Rheumatol 2024; doi:10.1002/art.42926 DOI: https://doi.org/10.1002/art.42926

Morand EF, Vital EM, Petri M, van Vollenhoven R, Wallace DJ, Mosca M, et al. Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 3 trial (SLE-BRAVE-I). Lancet. 2023;401(10381):1001-1010. doi: 10.1016/S0140-6736(22)02607-1 DOI: https://doi.org/10.1016/S0140-6736(22)02607-1

Petri M, Bruce IN, Dorner T, Tanaka Y, Morand EF, Kalunian KC, et al. Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 3 trial (SLE-BRAVE-II). Lancet. 2023;401(10381):1011-1019. doi: 10.1016/S0140-6736(22)02546-6 DOI: https://doi.org/10.1016/S0140-6736(22)02546-6

Isenberg D, Furie R, Jones NS, Guibord P, Galanter J, Lee C, et al. efficacy, safety, and pharmacodynamic effects of the Bruton’s tyrosine kinase inhibitor fenebrutinib (GDC-0853) in systemic lupus erythematosus: results of a Phase II, randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol. 2021;73(10):1835-1846. doi: 10.1002/art.41811 DOI: https://doi.org/10.1002/art.41811

Wallace DJ, Dorner T, Pisetsky DS, Sanchez-Guerrero J, Patel AC, Parsons-Rich D, et al. Efficacy and safety of the Bruton’s tyrosine kinase inhibitor evobrutinib in systemic lupus erythematosus: results of a Phase II, randomized, double-blind, placebo-controlled dose-ranging trial. ACR Open Rheumatol. 2023;5(1):38-48. doi: 10.1002/acr2.11511 DOI: https://doi.org/10.1002/acr2.11511

Furie RA, Bruce IN, Dorner T, Leon MG, Leszczynski P, Urowitz M, et al. Phase 2, randomized, placebo-controlled trial of dapirolizumab pegol in patients with moderate-to-severe active systemic lupus erythematosus. Rheumatology (Oxford). 2021;60(11):5397-5407. doi: 10.1093/rheumatology/keab381 DOI: https://doi.org/10.1093/rheumatology/keab381

Furie RA, van Vollenhoven RF, Kalunian K, Navarra S, Romero-Diaz J, Werth VP, et al. Trial of Anti-BDCA2 antibody litifilimab for systemic lupus erythematosus. N Engl J Med. 2022;387(10):894-904. doi: 10.1056/NEJMoa2118025 DOI: https://doi.org/10.1056/NEJMoa2118025

Werth VP, Furie RA, Romero-Diaz J, Navarra S, Kalunian K, van Vollenhoven RF, et al. Trial of Anti-BDCA2 antibody litifilimab for cutaneous lupus erythematosus. N Engl J Med. 2022;387(4):321-31. doi: 10.1056/NEJMoa2118024 DOI: https://doi.org/10.1056/NEJMoa2118024

Mackensen A, Muller F, Mougiakakos D, Boltz S, Wilhelm A, Aigner M, et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med. 2022;28(10):2124-2132. doi: 10.1038/s41591-022-02017-5 DOI: https://doi.org/10.1038/s41591-022-02017-5

Muller F, Taubmann J, Bucci L, Wilhelm A, Bergmann C, Volkl S, et al. CD19 CAR T-cell therapy in autoimmune disease - a case series with follow-up. N Engl J Med. 2024;390(8):687-700. doi: 10.1056/NEJMoa2308917 DOI: https://doi.org/10.1056/NEJMoa2308917

Schett G, Mackensen A, Mougiakakos D. CAR T-cell therapy in autoimmune diseases. Lancet. 2023;402(10416):2034-2044. doi: 10.1016/S0140-6736(23)01126-1 DOI: https://doi.org/10.1016/S0140-6736(23)01126-1

Downloads

Published

2024-09-17

How to Cite

1.
Clarke AE, Barber MR, Barr B, Cheema K, Li icholas L. Shifting Paradigms in the Treatment of Systemic Lupus Erythematosus. Can Rheumatol Today [Internet]. 2024 Sep. 17 [cited 2024 Nov. 21];1(2):4–16. Available from: https://canadianrheumatologytoday.com/article/view/1-2-Clarke_et_al

Issue

Volume 1, Issue 2, Summer 2024

Section

Articles

License

Copyright (c) 2024 Canadian Rheumatology Today

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.